1. Field:
This disclosure is concerned generally with therapy for Pseudomonas burn wound sepsis (PBWS) and specifically with the use of Pseudomonas immune globulin and ciprofloxacin as a combination therapy.
2. Prior Art:
Although infection with Pseudomonas aeruginosa (P. aeruginosa) is not common among the general population, P. aeruginosa infection is encountered very frequently in certain susceptible groups of patients. Burn victims and immunosuppressed cancer patients have been identified as having an unusually high risk of acquiring severe, and sometimes fatal, P. aeruginosa infection. P. aeruginosa infections are usually acquired during a hospital stay, not at home.
Bacterial infection is the leading cause of death among burn patients. (Monafo, W. W., 1979. An overview of infection control. J. Trauma 19 (Suppl): 879-80). Pseudomonas aeruginosa continues to be a major pathogen in burn infection. (McManus, W. F., C. W. Goodwin, A. D. Mason, Jr., and B. A. Pruitt. 1981. Burn Wound Infection. J. Trauma 21: 753-756). Numerous studies have demonstrated that pooled human IgG concentrates are protective in experimental Pseudomonas burn wound infection. For example, see Collins, M. S., and R. E. Roby. 1983. Anti-Pseudomonas aeruginosa activity of an antravenous human IgG preparation in burned mice. J. Trauma 23: 530-534. The development of IgG concentrates for intravenous infusion (IGIV) permits twice weekly infusion of 500 mg IgG/kg into burn patients without undesirable side effects. (Shirani, K. Z., G. M. Vaughan, A. T. McManus, B. W. Amy, W. F. McManus, B. A. Pruitt, and A. D. Mason. 1984. Replacement therapy with modified immunoglobulin G in burn patients: preliminary kinetic studies. Am. J. Med. 76(3A): 175-180). Our laboratory recently described an IGIV preparation enriched in antibodies to lipopolysaccharide (LPS) antigens of P. aeruginosa (PS-IGIV). PS-IGIV is prepared from plasma of donors that have naturally high levels of IgG antibody to LPS. (Collins, M. S., and R. E. Roby. 1984. Protective activity of an intravenous immune globulin (human) enriched in antibody against lipopolysaccharide antigens of Pseudomonas aeruginosa. Am. J. Med. 76(3A) 168-174). This strategy circumvents the need to immunize donors with experimental and potentially toxic vaccines. PS-IGIV is several-fold more potent than conventional IGIV in prophylaxis of experimental burn wound sepsis. In the therapy of established infection, combinations of PS-IGIV and tobramycin afford significantly greater survival in animal models than single agent therapy.
Nearly three decades ago it was reported that pooled human IgG is protective against experimental P. aeruginosa infection in normal and burned animals. (Fisher, M. W., and M. C. Manning. 1958. Studies on the immunotherapy of bacterial infections. I. The comparative effectiveness of human gammaglobulin against various bacterial species in mice. J. Immunol. 81: 29-31; and Rosenthal, S. M., R. C. Millican and J. Rust. 1957. A factor in human gamma-globulin preparations active against Pseudomonas aeruginosa infections. Proc. Soc. Exp. Biol. Med. 94: 214-217). Attempts in the 1960's to treat Pseudomonas infection with immune globulin were not very successful in part because of the limited amount of IgG that could be delivered by intramuscular injection of IgG concentrates. (Kefalides, N. A., J. A. Arana, A. Bazan, M. Bocanegra, P. Stastny, N. Velarde, and S. M. Rosenthal. 1962. Role of infection in mortality from severe burns: evaluation of plasma, gamma-globulin, albumin and saline solution therapy in a group of Peruvian Children, N. Engl. J. Med. 267: 317-323 and Stone, H. H., C. D. Graber, J. D. Martin, and L. Kolb. 1965. Evalulation of gamma globulin for prophylaxis against burn sepsis. Surgery 58: 810-814).
Passive protection studies using sera of animals immunized with LPS provide proof that IgG antibody to LPS is highly protective against P. aeruginosa in experimental infections. (Cryz, S. J., E. Furer, and R. Germanier. 1983. Protection against P. aeruginosa infection in a murine burn wound sepsis model by passive transfer of antitoxin A, antielastase and antilipopolysaccharide. Infect. Immun. 39: 1072-1079). The protective activity of IGIV in experimental P. aeruginosa infection prompted this laboratory to consider that an IGIV enriched in antibodies to LPS might be more protective than IGIV prepared from plasma of random donors. (Pollack, M. 1983. Antibody activity against P. aeruginosa in immune globulins prepared for intravenous use in humans. J. Infect. Dis. 147: 1090-1098). Accordingly, several thousand donors were tested by ELISA for IgG titers to LPS antigens of the seven Fisher-Devlin-Gnabasik (FDG) immunotypes of P. aeruginosa.
Approximately 5% of plasma donors had antibody titers .gtoreq.1:1,600 against FDG 1, 2, 4 and 6 LPS. Several hundred liters of plasma were obtained from ELISA tested donors, and PS-IGIV was produced. PS-IGIV is enriched from 4.84 to 11.72-fold in antibody to FDG 1, 2, 4 and 6 LPS (Table 1). Although not of intentional design, PS-IGIV is also enriched several-fold in IgG to FDG 3, 5 and 7. The present study indicates that PS-IGIV prophylaxis was protective in burned mice against all 18 clinical isolates examined. It should be noted that these 18 isolates were not preliminarily screened for sensitivity to IgG prophylaxis. Against 16 of these strains, the mean protective dose (PD.sub.50) of PS-IGIV was .ltoreq.100 mg IgG/kg body weight. PS-IGIV tended to be more protective against strains expressing FDG LPS antigens. Approximately 90% of P. aeruginosa strains isolated from serious infections fall within the FDG immunotype system (Fisher, M. W., H. B. Devlin and F. J. Gnabasik. 1969. New immunotype schema for P. aeruginosa based on protective antigens. J. Bacteriol. 98: 835-836).
Pseudomonas Immune Globulin, Intravenous (PS-IGIV) is currently in clinical trials in the US and Europe. PS-IGIV is prepared from plasma of donors that have naturally high levels of IgG antibody to lipopolysaccharide antigens of P. aeruginosa, as set forth in U. S. Pat. No. 4,587,121. It contains 5% IgG in 10% maltose and is prepared for intravenous infusion by a low pH process. The prophylactic activity of PS-IGIV is a burned mouse model was evaluated against 18 clinical isolates of P. aeruginosa representing 17 distinct International Antigenic Typing System serotypes. In burned mice challenged with approximately 10 to 100 mean lethal doses (LD.sub.50) the PD.sub.50 against the 18 strains ranged from less than 56 to 252 mg IgG/kg. In part, PS-IGIV protection may have resulted from neutralization of exotoxin A. In PS-IGIV treated mice challenged with 4 LD.sub.50 of exotoxin A, serum levels of aspartate and alanine aminotransferase were several-fold lower than those of mice treated with conventional IgG concentrates.
The present invention is not limited to the parenteral administration of PS-IGIV, but includes other immune globulin preparations, including but not limited to intramuscular preparations, intravenous preparations and hyperimmune globulins. Other immune globulin preparations, such as IgM preparations for intravenous and intramuscular administration may be effective, in combination therapy with quinoline derivatives such as ciprofloxacin in the treatment of burn wound sepsis.
Ciprofloxacin is a recently developed quinoline carboxylic acid derivative that is well absorbed when given orally and attains high concentrations in extravascular fluid. Ciprofloxacin is highly active against
P. aeruginosa in vitro (Chin, N., and H. C. Nev. 1984. Ciprofloxacin, a quinoline carboxylic acid compound active against aerobic and anaerobic bacteria. Antimicrob. Agents Chemother. 25: 319-326 and Eliopoulos, G. M., A. Gardella, and R. C. Moellering, Jr. 1984. In vitro activity of ciprofloxacin, a new carboxyquinoline antimicrobial agent. Antimicrob. Agents Chemother. 25: 331-335). Ciprofloxacin is active against P. aeruginosa pneumonia in guinea pigs (Schiff, J. B., G. J. Small, and J. E. Pennington. 1984. Comparative activities of ciprofloxacin, ticarcillin and tobramycin against experimental P. aeruginosa pneumonia. Antimicrob. Agents Chemother. 26: 1-4). In humans ciprofloxacin has been given orally at dosages ranging from 5.2 to 8.7 mg/kg/dose twice daily for seven days. This oral regimen appeared safe and led to serum levels of the drug that exceeded the in vitro MIC of ciprofloxacin against a large number of clinical strains of P. aeruginosa (Brumfitt, W., I. Franklin, O. Grady, J. M. T. Hamilton-Miller, and A. Iliffee. 1984. Changes in the pharmacokinetics of ciprofloxacin and fecal flora during administration of a 7-day course to human volunteers. Antimicrob. Agents Chemother. 26: 757-761).
P. aeruginosa is resistant to penicillin G. A combination of a P. aeruginosa specific penicillin and an aminoglycoside is the usual therapy for P. aeruginosa sepsis and has greatly contributed to the survival of patients, particularly leukemics. The management of P. aeruginosa in burn patients is also dependent upon topical antimicrobial therapy. But, the rapid emergence of antibiotic resistance by P. aeruginosa and the relatively high toxicity of potent anti-Pseudomonas agents such as aminoglycosides provide impetus to the continuing development and clinical evaluation of new therapeutic agents.
In addition to P. aeruginosa, a weakly virulent strain of Staphylococcus aureus (LD.sub.50 &gt;10.sup.8 cfu) has been found to greatly enhance the virulence of several strains of P. aeruginosa in experimental burn wound infection. Polymicrobial burn wound sepsis induced by approximately 100 cfu of P. aeruginosa and 50 cfu of S. aureus was found to be a lethal infection in challenged mice.